Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl]-8-azaspiro(4,5)-decane,7,9-dio ne, is disclosed in U.S. Pat. No. 3,717,634 as a pharmaceutically active compound which has been found to be effective for the treatment of anxiety disorders and depression. However, buspirone shows a very high first pass metabolism and only about 4% of the administered dose will reach the systemic circulation unchanged after oral administration (Mayol et al., Clin. Pharmacol. Ther., 37, 210, 1985). Great inter-individual variations in buspirone absorption have also been observed as demonstrated by variations of the maximum plasma concentration of drug by up to ten-fold (Gammans et al., American J. Med., 80, Suppl. 3B, 41-51, 1986). Metabolites have been identified, including several hydroxylated derivatives of buspirone that show low levels of pharmacological activity. The major metabolite, 1-(2-pyrimidinyl)-piperazine, (1-PP), has been found to demonstrate pharmacological activity in certain tests that suggest 1-PP itself possesses weak anxiolytic activity. However, in other tests 1-PP has shown that it antagonizes the desired anxiolytic and/or antidepressant action of buspirone.
The biological half-life of buspirone is very short and variable in man, on an order of 2-11 hours, whereas the major metabolite, 1-PP, has much slower elimination (Mayol et al., Clin. Pharmacol. Ther., 37, 210, 1985). These pharmacokinetic properties necessitate a daily dosing regimen requiring repeat administration which would be expected to have a negative effect on patient compliance. Since buspirone is rapidly absorbed after an oral dose, peak plasma values of unchanged drug occur shortly after drug administration. As buspirone blood levels decline, blood levels of 1-PP increase, giving much higher plasma levels of 1-PP. These high levels of 1-PP have been associated with the occurrence of undesired or adverse events observed during the first days of treatment. Such adverse effects can also seriously impact patient compliance due to resultant deliberate disruption of the drug therapy. Since its clinical introduction, buspirone has suffered from a perceived lack of rapid onset which may be attributable in part to patient compliance and/or variable metabolism.
The physicochemical, pharmacokinetic and pharmacological properties of drugs and their formulations often dictate how a drug should be used in a therapeutic situation. A drug characterized by a short biological half-life should usually be administered in short dosing intervals to maintain the plasma concentration levels that provide the pharmacologic action. As mentioned above, this often reduces patient compliance and as a result leads to underdosing between the dosage intervals. An ideal oral dosage form would be a once-daily formulation able to maintain the therapeutic drug levels in the body for 24 hours, yet without the risk of any adverse reactions.
Among formulations devised to avoid limitations due to a short biological half-life (rapid metabolism/elimination) have been various dosage forms which provide release of the desired drug over an extended period of time, thereby slowing the drug's absorption. Over the past two decades considerable progress has been made in developing controlled/extended release technologies for drug compounds. The design of various controlled/extended release formulations and their technologies are known in the art (L. Krowczynski, Extended Release Dosage Forms, CRC-Press Inc., USA, 1987, ISBN 0-8493-4307-0).
Some important advantages of such delivery systems can be:
reduction of the frequency of dosing (with a concomitant increase in patient compliance); PA1 maintenance of therapeutic plasma drug levels for a longer period of time than would be indicated by the drug's biological half-life; PA1 reduction of undesired adverse reactions/toxicity (by suppression of the initial high plasma concentration peaks of drug/metabolite); and, in some instances, PA1 reduction of the amount of drug required for treatment (by reduction of the initial high concentration spike and rapid elimination of drug).
In order to capture these advantages, controlled/extended release formulations of buspirone and its salts were developed and disclosed in U.S. Pat. No. 5,431,922. Although the initial objectives for these buspirone extended release formulations were realized; e.g. an improved pharmacokinetic profile for buspirone blood levels, reduction of 1-PP peak blood levels, and increased time intervals between dosing; a high level of variability in the pharmacokinetic parameters, particularly with buspirone and 1-PP blood levels over time, between dosing periods and between patients became problematic. To this point in time, the formulations that were the subject of U.S. Pat. No. 5,431,922 have not been commercialized.
Recently, a method for increasing bioavailability of orally administered hydrophobic pharmaceutical compounds was disclosed in WO 95/20980. The method comprises concurrent administration of a compound that inhibits cytochrome P4503A enzymes or P-glycoprotein-mediated membrane transport. While lists of compounds that can be substrates and compounds that can act as inhibitors were disclosed, neither buspirone nor nefazodone was mentioned. The only inhibitor exemplified was ketoconazole.
Nefazodone has been disclosed as being an inhibitor of cytochrome P4503A4. Recently a letter to the editor in J. Clin. Psychiatry, 57:7, July 1996, referred to nefazodone's reported inhibition of cytochrome P4503A3/4 and its related effect of increasing the concentration and toxicity of alprazolam and triazolam. Further study was recommended in order to determine whether this inhibitory effect on cytochrome by nefazodone might represent a therapeutic asset by increasing/stabilizing plasma concentrations of certain CYP3A3/4 substrates.
Other reports of a differing drug interaction effect have appeared over the past few years. These reports suggest that several agents, one being buspirone, have been effective in augmentation of an antidepressant effect when co-administered with an antidepressant drug regimen such as fluoxetine. A pharmacokinetic study of the co-administration of nefazodone with buspirone was undertaken as a preliminary step to clinically study augmenting effect on the antidepressant drug nefazodone. An striking result was observed: concurrent administration of nefazodone with buspirone demonstrated that nefazodone had a marked effect on buspirone and 1-PP pharmacokinetics.
Nothing in the previous references or prior art has disclosed or suggested the advantageous improvements in oral buspirone's pharmacokinetics and metabolism resulting from concomitant administration of the antidepressant drug nefazodone.